As a physician-scientist dedicated to improving the health of children, the candidate seeks to establish an independent research career investigating the disruptions of T cell development and regulation that lead to susceptibility to infection or autoimmunity. To this end, the candidate and her mentor, Paul M. Allen, at the Washington University in St. Louis, have established a research project addressing molecular mechanisms underlying T cell development. The adaptive immune response requires the generation of T cells during thymic development. The process of positive selection is critical to thymic development and is dependent upon both T cell receptor (TCR) signaling and chemokine-mediated migration. We hypothesize that TCR and chemokine receptor signals are integrated during positive selection. We have developed two complementary model systems to test this hypothesis. Generation of TCR transgenic mice deficient for the signaling molecule protein kinase C ? (PKC?) revealed diminished positive selection due to diminished TCR signaling. Generation of TCR transgenic mice deficient for the actin-binding protein L-plastin revealed diminished thymocyte motility towards chemokine. The aims of this application are to define the molecular mechanism by which PKC? regulates positive selection, to investigate whether inefficient TCR signaling alters the changes in chemokine motility induced by positive selection, and to determine whether diminished thymocyte motility alters TCR signaling and positive selection. This research project will enable the candidate to draw upon the expertise of the Allen laboratory and the rich environment of the Department of Pathology and Immunology at the Washington University in St. Louis to develop the technical skills and intellectual rigor required to launch an independent research program. With the mentorship of Paul M. Allen, the assembled advisory committee of distinguished immunologists, and participation in the classes and seminars at Washington University, the candidate will be able to successfully transition from a mentored position to an independent investigator. To remain cognizant of the clinical relevance of ongoing research, the candidate will also spend a small portion of her time delivering care to sick children as a specialist in Pediatric Infectious Diseases. RELEVANCE: Patients who cannot correctly produce T cells, a kind of white blood cell, suffer from increased susceptibility to infection and to autoimmune diseases. This research project seeks to increase our understanding of how T cells are produced. Results from this research could be applied to the diagnosis and management of patients with deficiencies in their immune system and possibly to patients with autoimmune diseases.